rs17636067

Positions:

chr8-18057617-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_177924.5(ASAH1):c.1105G>A(p.Val369Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,598,538 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V369A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0041 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 45 hom. )

Consequence

ASAH1
NM_177924.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.09

Variant links:

Genes affected

ASAH1 (HGNC:735): (N-acylsphingosine amidohydrolase 1) This gene encodes a member of the acid ceramidase family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. Processing of this preproprotein generates alpha and beta subunits that heterodimerize to form the mature lysosomal enzyme, which catalyzes the degradation of ceramide into sphingosine and free fatty acid. This enzyme is overexpressed in multiple human cancers and may play a role in cancer progression. Mutations in this gene are associated with the lysosomal storage disorder, Farber lipogranulomatosis, and a neuromuscular disorder, spinal muscular atrophy with progressive myoclonic epilepsy. [provided by RefSeq, Oct 2015]

ASAH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_177924.5

BP4

Computational evidence support a benign effect (MetaRNN=0.0107887685).

BP6

Variant 8-18057617-C-T is Benign according to our data. Variant chr8-18057617-C-T is described in ClinVar as [Benign]. Clinvar id is 362373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-18057617-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00407 (619/152246) while in subpopulation EAS AF= 0.0232 (120/5182). AF 95% confidence interval is 0.021. There are 5 homozygotes in gnomad4. There are 337 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASAH1	NM_177924.5 linkuse as main transcript	c.1105G>A	p.Val369Ile	missense_variant	14/14	ENST00000637790.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASAH1	ENST00000637790.2 linkuse as main transcript	c.1105G>A	p.Val369Ile	missense_variant	14/14	1	NM_177924.5	P2	Q13510-1

Frequencies

GnomAD3 genomes

AF:

0.00405

AC:

616

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0229

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.0229

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00877

AC:

2200

AN:

250950

Hom.:

AF XY:

0.00709

AC XY:

962

AN XY:

135618

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.0376

Gnomad ASJ exome

AF:

0.00298

Gnomad EAS exome

AF:

0.0330

Gnomad SAS exome

AF:

0.000918

Gnomad FIN exome

AF:

0.00347

Gnomad NFE exome

AF:

0.000846

Gnomad OTH exome

AF:

0.00718

GnomAD4 exome

AF:

0.00238

AC:

3447

AN:

1446292

Hom.:

Cov.:

AF XY:

0.00215

AC XY:

1545

AN XY:

719872

show subpopulations

Gnomad4 AFR exome

AF:

0.000755

Gnomad4 AMR exome

AF:

0.0374

Gnomad4 ASJ exome

AF:

0.00306

Gnomad4 EAS exome

AF:

0.0223

Gnomad4 SAS exome

AF:

0.000895

Gnomad4 FIN exome

AF:

0.00457

Gnomad4 NFE exome

AF:

0.000285

Gnomad4 OTH exome

AF:

0.00339

GnomAD4 genome

AF:

0.00407

AC:

619

AN:

152246

Hom.:

Cov.:

AF XY:

0.00453

AC XY:

337

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00164

Gnomad4 AMR

AF:

0.0230

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.0232

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.00283

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.00275

Hom.:

Bravo

AF:

0.00608

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00719

AC:

873

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 2020	This variant is associated with the following publications: (PMID: 29140481) -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 30, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	ASAH1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2015	- -

Farber lipogranulomatosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

ASAH1-related disorders

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;T;T;.;T;T;T;T;T;T;T;.;.;.

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.65

LIST_S2

Uncertain

0.86

.;D;D;D;D;.;D;D;D;D;D;D;D;D

MetaRNN

Benign

0.011

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.7

L;L;.;.;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.83

.;N;N;N;.;.;.;.;.;.;.;.;.;N

REVEL

Benign

0.24

Sift

Benign

0.064

.;T;T;D;.;.;.;.;.;.;.;.;.;T

Sift4G

Benign

0.17

.;T;T;T;.;.;.;.;.;.;.;.;.;T

Polyphen

0.92

P;P;D;P;.;.;.;.;.;.;.;.;.;.

Vest4

0.052, 0.076, 0.070, 0.081

MVP

0.79

MPC

0.0036

ClinPred

0.011

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.053

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over